Slo2 channels are high-conductance potassium channels widely expressed in the mammalian nervous system. They play important roles in controlling neuronal excitability by allowing a large outward current through the cell membrane. Recent studies have established a strong link between mutations of human Slo2 channels and epileptic disorders. The expression and physiological function of a potassium channel in vivo generally depend on a variety of regulatory proteins. With respect to Slo2 channels, however, very little is known about the regulatory proteins. The nematode C. elegans has a single mammalian Slo2 channel homologue known as SLO-2, which is also widely expressed in the nervous system and plays important roles in regulating neuronal functions. This project is to take advantage of the exceptional power of C. elegans molecular genetics to identify proteins that are important to SLO-2 function in vivo. Through a genetic screen for mutants that suppressed a lethargic phenotype caused by expressing a hyperactive SLO-2 in worms, two proteins (RSE-1 and ADR-1) were identified as novel regulators of SLO-2. RSE-1 is a homologue of human heterogeneous nuclear ribonucleoprotein U (hnRNP U) whereas ADR-1 is a homologue of human adenosine deaminases acting on RNA (ADARs). Both hnRNP U and ADARs have been implicated in neurological diseases including epilepsy but the mechanisms are unclear. A combination of electrophysiological, molecular biological and genetic approaches will be used to achieve three specific objectives: (1) understanding how RSE-1 controls SLO-2 expression; (2) understanding how ADR-1 modulates SLO-2 function; and (3) identifying additional molecules important to SLO-2 regulation in vivo. The long-term goal is to use new knowledge from worms to uncover novel human Slo2 channel regulators, and to elucidate how they contribute to physiological functions or pathological roles of human Slo2 channels.